In a considerable number of breast cancer patients, cancer cells can transfer from the breast tissue to other parts of the body through the bloodstream. At these sites, they may remain in a clinically undetectable dormant state for a long period of time. And then suddenly become metastatic cancer cells. It is difficult to predict whether and when the transfer will occur.
Cell biologist Mina Bissell said: "Our research shows that the stable microvascular system constitutes a dormant microenvironment, and the germinated new vascular system stimulates micrometastasis. Vessel germination was originally intended to meet the needs of tissue growth. But if the tumor cell happens to be in the wrong place at the wrong time, it will begin to grow under the influence of cell-derived factors at the endothelial tip. "
Bissell said: "Some patients may have metastatic relapses within a few months, while others may have distant relapses after several years or even decades. Recent studies have found that disseminated tumor cells arrive Before or at the time, the metastatic microenvironment has been established at the distal site, which can be used to explain the early recurrence of cancer cells. Behavior is a big problem. "
In previous studies, Bissell and his team confirmed that the basement membrane surrounding the mammary glands and other epithelial tissues provides a microenvironment that induces normal epithelial cells and dormant tumor cells to be at rest. In view of the fact that breast cancer cells must first pass through the basement membrane microvasculature before they can move from the bloodstream to the secondary site-breast cancer usually mostly transfers to the lung, bone marrow, brain, and liver. Bissell and biological engineer Cyrus Ghajar suspect that the basement membrane may be the main component of the dormant microenvironment of the remote organs.
To test this idea, the researchers used two mouse models of human breast cancer metastasis to carry out research and confirmed that dormant tumor cells settled on the membrane microvasculature of the lung, bone marrow and brain tissue. To determine whether endothelial cells directly affected the growth of breast cancer cells, they then constructed a unique model of the lung and bone marrow microvascular microenvironment with organ characteristics. In these models, endothelial cells formed blood vessel-like structures, and when tumor cells were placed on these blood vessel-like structures, the researchers reproduced the results observed in vivo.
Using their organ characteristic models, Ghajar, Bissell and collaborators discovered that the thrombospondin-1 protein, which is ubiquitous in the stable microvasculature, produced a dormant microenvironment by inhibiting the growth of breast cancer cells. When the tips of these vascular cells begin to germinate, the thrombospondin-1 protein gives way to the TGF-Î²1 and periostin proteins in the new vascular system, transforming the dormant microenvironment into a metastatic environment, which not only allows and promotes the growth of breast cancer cells.
Ghajar said: "Our research defines the dormant microenvironment on the basis of cells and molecules for the first time. What is interesting is that we found that the culprit is actually the microvascular endothelium that we usually identify as passive bystanders. Like most biological processes, homeostasis is the key. In this case, the destruction of the stable vascular endothelium can destroy this dormant internal environment and promote the formation of a microenvironment that stimulates micro-transfer growth. "
Ghajar said that identifying the dormant microenvironments in the basement membrane microvasculature and the mechanism by which these microenvironments are transformed into metastatic microenvironments in the neovascular system has important implications for future breast cancer treatment. In addition, this unique organ characteristic model developed in the new research also brings hope for future therapeutic research.
Ghajar, Bissell and colleagues are now investigating whether these breast cancer findings are also applicable to other tumor types and secondary metastatic tissues. They are also trying to determine the mechanism of tumor dormancy specific to other tissues.
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